Antitumor agents

Abstract

The invention provides compounds of formula I: wherein Y is F, Cl, Br, methyl or methoxy; and pharmaceutically acceptable salts thereof. The compounds are effective antitumor agents. The invention also provides pharmaceutical compositions comprising a compound of formula I or a salt thereof, intermediates useful for preparing a compound of formula I, and therapeutic methods comprising administering a compound of formula I or a salt thereof to a mammal in need thereof.

1. A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 Y is F, Cl, Br, methyl or methoxy; and 
 Z is a Na cation, K cation, Li cation, Rb cation, Cs cation, Ca cation, or Mg cation. 
 
     
     
       2. The compound of  claim 1  wherein Y is Cl or Br. 
     
     
       3. The compound of  claim 2  wherein Z is a sodium cation or a potassium cation. 
     
     
       4. The compound of  claim 3  wherein the configuration of the carbon indicated by the asterisk in formula I is the (R) configuration. 
     
     
       5. The compound of  claim 4  wherein the compound is (R) 2[4-(7-chloroquinolin-2-yloxy)phenoxy]propionic acid sodium salt. 
     
     
       6. The compound of  claim 4  wherein the compound is (R) 2[4-(7-bromoquinolin-2-yloxy)phenoxy]propionic acid sodium salt. 
     
     
       7. A composition comprising the compound of  claim 1  in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
       8. A composition comprising the compound of  claim 3  in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
       9. A composition comprising the compound of  claim 4  in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
       10. A method for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein Y is F, Cl, Br, methyl or methoxy; or a pharmaceutically acceptable salt thereof,
 comprising contacting a compound of formula II: 
 
       
         
           
           
               
               
           
         
       
       wherein Y is F, Cl, Br, methyl or methoxy, with a compound of formula III: 
       
         
           
           
               
               
           
         
       
       in the presence of a base and a solvent to form a mixture;
 heating the mixture; and 
 contacting the mixture with an acid, to provide the compound of formula I. 
 
     
     
       11. The method of  claim 10  wherein Y is F, Cl or Br. 
     
     
       12. The method of  claim 10  wherein Y is —OMe or methyl. 
     
     
       13. The method of  claim 10  wherein the configuration of the carbon indicated by the asterisk in formula I is the (R) configuration. 
     
     
       14. The method of  claim 10  wherein the configuration of the carbon indicated by the asterisk in formula I is the (S) configuration. 
     
     
       15. The method of  claims 11  wherein the compound of formula I is 2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
       16. The method of  claim 11  wherein the compound of formula I is (R) 2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
       17. The method of  claim 10  wherein the base comprises sodium hydride or potassium carbonate, the solvent comprises dimethylformamide, and the heating is carried out under refluxing conditions. 
     
     
       18. The method of  claim 10  wherein the acid is aqueous hydrochloric acid. 
     
     
       19. The method of  claim 10  further comprising purifying the compound of formula I by chromatography or crystallization.